ABSTRACT/PROJECT SUMMARY This PPG team (funded through P01 DK113954) has been working on an integrated set of studies to reveal the fundamental functions and mechanisms of the steroid receptor coactivator (SRC) family of proteins, namely, SRC-1, -2 and -3, in system metabolism, with Project #1 particularly focusing on brain SRCs. Recent discoveries (detailed below) revealed a potential link between brain SRC-1 and Alzheimer?s disease (AD), and therefore we seek this administrative supplement to support pilot studies for this additional direction. We demonstrated that deletion of SRC-1 significantly reduces brain expression of neurogranin, which is a synaptic protein associated with early synaptic dysfunctions in AD. Since loss of neurogranin causes learning/memory deficits, recapitulating cognitive decline in AD patients, we examined a potential role of SRC-1 in the regulation of cognitive behaviors. We found that mice carrying a SRC-1 loss-of-function mutation (SRC-1L1376P) displayed impaired contextual fear memory, suggesting that SRC-1 functions are required for normal cognition. These pilot observations support a hypothesis that brain SRC-1 regulates cognition and is a potential target for AD treatment when dysfunctional. However, some key preliminary studies are still needed to provide the necessary scientific premise for this hypothesis. Thus, we seek this administrative supplement to support the following studies. First, we plan to systemically characterize cognitive behaviors of SRC-1 knockout mice and SRC-1L1376P mutant mice. In addition, the PPG team has identified a SRC stimulator, MCB-613, and recently demonstrated that this compound can pass the blood-brain-barrier to act in the brain. Thus, the second study is to determine whether MCB-613 can improve cognitive functions and reduce A? deposition in a pre-clinical AD mouse model. These studies will provide necessary ground work for a number of future studies, including (1) examining impacts of SRC-1 deletion/mutation on cognition in 2 and 3-year old mice, (2) identifying the critical SRC-1-expressing neural populations (e.g. hippocampus, amygdala) responsible for cognitive controls, (3) delineating how SRC-1 coactivates multiple NRs to regulate expression of neurogranin (or other AD-associated genes), (4) exploring the role of SRC-2 and SRC-3 on cognitive behaviors, and (5) exploring effects of MCB-613 in other AD models (e.g. 2-year old mice, or tau-related AD models). We will then seek other funding mechanisms (e.g. R01) to support these future studies.